Real-world outcomes among patients with HER2+ metastatic breast cancer with brain metastases

BACKGROUND: Among patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC), incidence of brain metastases (BMs) is relatively high and increasing. Despite the high unmet need for patients with HER2+ MBC and BMs, real-world data on treatment patterns and outcomes for these patients are limited. OBJECTIVE: To compare treatment patterns and overall survival (OS) among patients with HER2+ MBC with and without BMs in the United States. METHODS: This was a real-world retrospective cohort study in which adults diagnosed with HER2+ MBC between January 1, 2016, and May 31, 2019, were identified in the Flatiron Health electronic health records database. The cohort was stratified by presence of BMs at MBC diagnosis (baseline) and before the initiation of each line of therapy (LOT). Key outcomes were OS and systemic therapy/regimen used within each LOT. An adjusted Cox proportional hazards model was used to evaluate the impact of BMs on OS. RESULTS: Of 1,755 included patients, 173 (9.9%) had BMs at baseline. Trastuzumab+ pertuzumab–based regimens were the most common first- (n = 689, 44.3%) and second-line (n = 316, 35.3%) treatments for all patients. Among patients with BMs, trastuzumab emtansine was the most common third-line regimen (n = 18, 23.4%). Lapatinib-based regimens were used more frequently among patients with BMs but were used by less than 20% of patients with BMs within any LOT. Median OS was 22.3 and 37.3 months for patients with and without BMs at baseline, respectively. Patients with BMs had a higher risk of death compared with patients without BMs (HR, 3.2; 95% CI = 2.6-3.8). CONCLUSIONS: BMs are associated with an increased risk of mortality among patients with HER2+ MBC. Further studies are needed to evaluate the extent to which novel systemic therapies for HER2+ MBC address the unmet need among patients with BMs.

RESULTS: Of 1,755 included patients, 173 (9.9%) had BMs at baseline. Trastuzumab + pertuzumab-based regimens were the most common first-(n = 689, 44.3%) and second-line (n = 316, 35.3%) treatments for all patients. Among patients with BMs, trastuzumab emtansine was the most common third-line regimen (n = 18, 23.4%). Lapatinib-based regimens were used more frequently among patients with BMs but were used by less than 20% of patients with BMs within any LOT. Median OS was 22.3 and 37.3 months for patients with and without BMs at baseline, respectively. Patients with BMs had a higher risk of death compared with patients without BMs (HR, 3.2; 95% CI = 2.6-3.8).

CONCLUSIONS:
BMs are associated with an increased risk of mortality among patients with HER2+ MBC. Further studies are needed to evaluate the extent to which novel systemic therapies for HER2+ MBC address the unmet need among patients with BMs.

Plain language summary
Of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer that had spread, in 10% it had spread to their brain when diagnosed. National Comprehensive Cancer Network (NCCN) Central Nervous System guidelines recommend systemic tucatinib-or lapatinib-based treatment for patients with cancer that has spread to their brain. Overall, 40% received recommended treatments, but only 20% of those with cancer that had spread to their brain. Patients with cancer that had spread to their brain were more likely to die sooner.

Implications for managed care pharmacy
In this real-world study of patients with HER2+ metastatic breast cancer (MBC), 10% had brain metastases (BMs) at diagnosis. Overall, less than 20% of patients with BMs received the NCCNrecommended regimens. Patients with BMs had shorter overall survival and a 3-fold greater risk of death, highlighting the greater disease burden and unmet need in patients with HER2+ MBC and BMs.
Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide and is the leading cause of cancer death in women. 1 In the United States, there were an estimated 276,480 new cases of BC and 42,170 BC deaths in 2020. 2 The human epidermal growth factor receptor 2-positive (HER2+) BC subtype is an aggressive form of the disease associated with an increased likelihood of recurrence and metastasis. 3 Approximately 15% of women diagnosed with early (stages 1-3) BC and 26% of women diagnosed with metastatic disease have the HER2+ molecular subtype. 4 Among BC subtypes, incidence of brain metastases (BMs) is highest for HER2+ and triple-negative BC. 5 Evidence suggests that up to 50% of patients with HER2+ BC will develop brain or central nervous system (CNS) metastases over the course of their disease 6-9 ; however, because screening of asymptomatic patients for BMs is not recommended in clinical practice, the incidence of BMs is likely underestimated. 10-12 Since the introduction of systemic HER2-directed agents for BC, which are now standard of care, the incidence of BMs has been increasing in patients with HER2+ metastatic breast cancer (MBC). 7,13 This is hypothesized to be due to multiple factors, including improved systemic disease and a lack of HER2-directed therapies that effectively penetrate the blood-brain barrier to delay the development of BMs. Additionally, there is a biological predisposition of HER2+ tumors to metastasize to the brain. 14,15 As patients with HER2+ MBC live longer as a result of systemic therapies, there is more time for development of BMs. [14][15][16] Current treatment approaches for patients with HER2+ MBC and BMs include the use of systemic therapies recommended for HER2+ MBC and local therapies such as surgical resection, stereotactic radiosurgery/radiotherapy (SRS), and whole-brain radiation therapy (WBRT). [10][11][12][17][18][19] Surgical resection may be followed by SRS or WBRT for improved local control. 19-21 However, patients who undergo WBRT often experience progressive and irreversible cognitive deterioration, including decline in learning capacity, processing speed, memory, and attention. 11,22 Seizures and balance disorders are also neurological sequelae from radiation therapy. 10,23-25 For some patients (eg, those with a limited number of BM lesions), SRS is preferred to WBRT as a less toxic local therapy option. 11,19 Local therapies are often added to systemic HER2-directed therapies. 26 In addition to the appropriate local therapy, clinical guidelines for management of advanced HER2+ BC with BMs recommend that patients whose systemic disease is not progressive at the time of BM diagnosis should remain on their current systemic therapy, whereas patients whose systemic disease is progressive at BM diagnosis should receive HER2directed therapy according to treatment algorithms. 10,11,18,19 The National Comprehensive Cancer Network (NCCN)recommended first-line (1L) standard of care for patients with HER2+ MBC is trastuzumab + pertuzumab in combination with a taxane, followed by trastuzumab emtansine (T-DM1) in patients who progress after 1L treatment. 10,11,27 There is no established standard of care in third-line (3L) treatment; however, other treatment options include lapatinib + trastuzumab or capecitabine, as well as trastuzumab with chemotherapy. 10, 11,27 Despite improvements in outcomes with the widespread use of targeted therapies for HER2+ MBC in recent decades, prognosis after a diagnosis of BMs remains poor. 16 In the Systemic Therapies for HER2-positive Metastatic Breast Cancer (SystHERs) study, a prospective cohort of HER2+ MBC patients (N = 977) in the United States enrolled from 2012 to 2016, the risk of death was higher in patients with CNS metastases at diagnosis vs patients who never developed CNS metastases (hazard ratio [HR] = 2.86; 95% CI = 2.05-4.00). 8 Additionally, progression of BMs/CNS metastases is the cause of death among 61%-70% of HER2+ MBC patients with BMs/CNS metastases. 28,29 Symptoms (eg, seizures, visual impairment, headaches, nausea/vomiting) and neurological progression associated with BMs can be debilitating, affecting patients' health-related quality of life (HRQoL) and ability to carry out daily activities. 30 In the SystHERs study, patients with CNS metastases at MBC diagnosis reported lower HRQoL at enrollment, greater impairment in daily activities, and greater severity of cognitive dysfunction compared with patients without CNS metastases at diagnosis. 8 Despite the high unmet need among patients with HER2+ MBC and BMs, real-world data on treatment patterns and outcomes for these patients are limited. The objective of this study was to compare real-world treatment patterns and overall survival (OS) among HER2+ MBC patients in the United States with and without BMs.

STUDY DESIGN AND DATA SOURCE
This was a retrospective cohort study, as well as an exploratory treatment effectiveness study, using the Flatiron Health database (a nationwide, longitudinal, demographically and geographically diverse, deidentified database derived from electronic health record (EHR) data from more than 280 cancer clinics in the United States). 31 Flatiron's Enhanced Metastatic Breast Cancer Datamart includes structured data (eg, laboratory values, prescribed drugs), in addition to unstructured data (eg, biomarker levels), collected via technology-enabled chart abstraction from physician's notes

LOT AND TREATMENT REGIMEN DEFINITIONS
Flatiron Health's LOT rules were used to characterize treatment patterns. 31 Flatiron defines each LOT as the first eligible drug episode plus other eligible drugs administered within 28 days. An "episode" of systemic therapy is defined as an administration or a noncanceled order for nonabstracted therapies. If a patient was prescribed 2 or more of the hormone therapies letrozole, anastrozole, exemestane, or tamoxifen in a LOT, only 1 is included in the LOT according to which was received last in the 28-day period. This same rule applies to patients who receive 2 or more lines of leuprolide, goserelin, or triptorelin.
Treatment regimens in each LOT were categorized into mutually exclusive groups on a hierarchical basis: "trastuzumab + pertuzumab-based" regimens were defined as receipt of trastuzumab + pertuzumab in the same line but no lapatinib or T-DM1; "trastuzumab-based" regimens were defined as receipt of trastuzumab in a line but no pertuzumab, lapatinib, or T-DM1; "T-DM1-based" regimens were defined as receipt of T-DM1 in a line but no pertuzumab, trastuzumab, or lapatinib; "lapatinib-based" regimens were defined as receipt lapatinib in a line but no trastuzumab, pertuzumab, or T-DM1; and "hormone + chemotherapy" regimens were defined as receipt of hormone therapy + chemotherapy in the same line but no trastuzumab, pertuzumab, T-DM1, or lapatinib. If patients received only hormone therapy or only chemotherapy in a line, the regimen was categorized as "hormone" or "chemotherapy," respectively. All other combinations were categorized as "other."

COVARIATES
Covariates of interest included sex, age, race and ethnicity, stage of initial BC diagnosis, de novo or recurrent identified based on the evidence of BMs in Flatiron's abstracted sites of metastasis table extracted from patients' EHR records. Outcomes were assessed based on presence of BMs at MBC diagnosis (baseline) as well as before the initiation of each line of therapy (LOT). Patients were followed until their last activity date, at which point they were censored. No exclusion criteria were applied to the cohort and clinical trial patients were not excluded from the study. and other unstructured documents. Institutional review board approval was not required, as the study was noninterventional and only deidentified patient records were used.

PATIENT POPULATION
The study included patients diagnosed with HER2+ MBC between January 1, 2016, and May 31, 2019, who were aged 18 years or older at diagnosis and had follow-up on or after their MBC diagnosis date. Patients with BMs were  Over the study period, we observed an increase in the percentage of patients who progressed from early BC presenting with BMs as the first site of metastasis (10.5% in 2016 to 18.4% in 2019) ( Figure 1).
The data that support the findings of this study were obtained under license from Flatiron Health, New York, NY, and are not publicly available.

TREATMENT PATTERNS
The most common 1L and second-line (2L) treatments for all patients were trastuzumab + per tuzumab-based regimens (1L, n = 689 patients, [

STATISTICAL ANALYSIS
Descriptive statistics for continuous variables included mean, median, SD, and IQR. Categorical variables were presented as frequency counts and percentages. Survival analyses were MBC at baseline, Eastern Cooperative Oncology Group performance status (ECOG PS) score, hormone receptor status, and number and sites of metastases at baseline.

OUTCOMES
The primary outcome of interest was OS, defined as time from baseline to death or last visit date. Patients without a death recorded during follow-up were censored at their last activity date. Patient mortality data are verified within the Flatiron dataset by cross-checking of both EHR

Discussion
This real-world retrospective study examined treatment patterns and OS in patients with HER2+ MBC with and without BMs from January 2016 to May 2019. Our results indicate that treatment patterns in this population are heterogeneous, especially in later lines of therapy. Overall, higher use of trastuzumab + pertuzumab-based therapy in 1L is consistent with current international clinical practice guideline recommendations. 10,11,27 Trastuzumab + pertuzumab-based regimens were most commonly used in 1L and 2L, and use was greater among patients without BMs compared with patients with BMs (44.9% vs 38.2% in 1L, respectively). In 3L, T-DM1-based therapy was most common for patients with BMs, whereas trastuzumab-based therapy was the most common for patients without BMs. Trastuzumab-based therapy was used most commonly for all patients in 4L and 5L. Overall, there was a high use of trastuzumab in all lines of therapy in both cohorts. Although lapatinib + capecitabine is a recommended regimen for HER2+ patients with BMs, 19 lapatinib-based regimens were used by less than 20% of patients with BMs within any LOT. Our treatment pattern findings are generally consistent with those observed in other real-world studies. In the SystHERs registry, trastuzumab + pertuzumab-based therapy was also the most common 1L regimen. Relative to our findings of 1L use, a higher proportion of patients in the SystHERs registry received a trastuzumab + pertuzumab-based regimen: 52.9% and 74.8% with and without CNS metastases at diagnosis, respectively. 8 Also similar to our findings, compared with patients without CNS metastases at diagnosis, a smaller proportion of patients with CNS metastases at diagnosis received trastuzumab (92.8% and 70.1%, respectively) and a larger proportion of NCCN guidelines recommend this regimen for 1L, and trastuzumab deruxtecan and T-DM1 are recommended 2L treatments. In both 1L and 2L, the proportion of patients using trastuzumab + pertuzumab-based regimens was higher for patients without BMs compared with patients with BMs (1L, 44.9% vs 38.2% and 2L, 36.9% vs 25.2%, respectively) ( Figure 2). Although the NCCN guidelines for HER2+ MBC do not specify recommended treatments for patients with BMs, the NCCN CNS guidelines recommend systemic treatment with tucatinib-or lapatinib-based regimens. The most common 3L therapies were T-DM1-based regimens (n = 18, 23.4%) among patients with BMs and trastuzumab + pertuzumab-based regimens (n = 90, 24.6%) among patients without BMs, though NCCN guidelines recommend T-DM1 in 2L. Trastuzumab-based regimens, which are included in NCCN guidelines for later lines of therapy, were the most commonly used therapies for patients with and without BMs in both the fourth-line (4L) (25.0% and 24.1%, respectively) and fifth-line (5L) (36.4% and 29.2%, respectively) therapies. In 1L through 4L, lapatinib-based regimens were used more frequently among patients with BMs, in line   35 Our study findings showed that the proportion of BMs as the first site of metastasis increased during the study period from 10.5% to 18.4%.
Recent studies of novel therapies for the treatment of HER2+ MBC have explored outcomes among patients with CNS metastases/BMs. [36][37][38] For example, in the phase 3 NALA clinical trial of neratinib + capecitabine vs lapatinib + capecitabine in patients with HER2+ MBC previously treated with 2 or more HER2-directed regimens, time to intervention (most commonly radiotherapy) for symptomatic CNS disease was delayed with neratinib + capecitabine compared with lapatinib + capecitabine (cumulative patients received lapatinib (2.5% and 23.0%, respectively) as part of their 1L regimen. Shewade et al examined 1L treatment following diagnosis of CNS metastases among patients with HER2+ MBC and found that the most common treatments were trastuzumab + pertuzumab-containing (25.8%) or trastuzumab-containing (15.0%) regimens. 33 Lapatinib-containing (20.5%) and T-DM1-containing (16.7%) regimens were also commonly used. Relative to our findings among patients with BMs in 1L, use of trastuzumab + pertuzumab-containing regimens was somewhat lower and use of lapatinib-and T-DM1-containing regimens was higher in this study.
We also observed that risk of death among patients with BMs was 3 times higher than risk of death among patients without BMs, which is consistent with findings from the SystHERs registry study, in which patients with CNS metastases at MBC diagnosis had significantly shorter median OS and almost 3 times higher risk (HR = 2.86) of death than those who never developed CNS metastases. 8  42 In another exploratory analysis of HER2CLIMB patients, time to new brain lesions or death was reduced by 48% in the tucatinib arm (HR = 0.52; 95% CI = 0.33-0.82; P = 0.005). 43 To date, this is the first regimen to demonstrate improved antitumor activity in patients with HER2+ MBC and BMs in a randomized controlled trial. Given the evolving treatment landscape for HER2+ MBC patients, including those with BMs, further real-world studies are needed to understand how new and emerging therapies will influence treatment patterns and outcomes for patients with HER2+ MBC and BMs.

LIMITATIONS
The primary limitation of this study is that the validity of our findings depend on the completeness of treatment records and documentation. Additionally, there is potential for misclassification of LOT because of Flatiron Health's rule-based algorithm. However, we would expect this to be nondifferential in nature. Inherent to real-world data is the possibility of misclassification, both for death and BMs. However, these would both be nondifferential in nature and would, therefore, result in an attenuated effect estimate. Additionally, a previously published validation analysis of mortality endpoint reporting by Flatiron reported a sensitivity of 97.7% for patients with MBC, suggesting that any misclassification of death is unlikely to have significantly impacted the outcomes of this study. 44   Overall Survival by the Presence of BMs at Baseline BMs = brain metastases.